Absorption, distribution and excretion of 14C-chloroquine after single oral administration in albino and pigmented rats: binding characteristics of chloroquine-related radioactivity to melanin in-vivo.

Chloroquine is an antimalarial agent that has been reported to have distinct affinity to melanin. After single oral administration of 14C-chloroquine at a dose of 20mg kg-1 under non-fasting conditions, the absorption, distribution and excretion of 14C-chloroquine-related radioactivity were studied in albino and pigmented rats. The objectives of the study were to investigate differences in the disposition of chloroquine between albino and pigmented rats and to define its in-vivo binding characteristics to melanin-containing ocular tissues. Extensive uptake of radioactivity into tissues was indicated by higher concentrations in most tissues compared with serum and there was no quantitative differences in the distribution of radioactivity found between albino and pigmented rats except for melanin-containing tissues, such as the uveal tract of the eye and perhaps hair follicles. There was selective and strong binding of drug-related compounds to these tissues in pigmented rats. The uveal tract concentrations reached the maximum value of 158.42 +/- 7.86 micrograms equiv g-1 (mean+/-s.e.) at 1 week and decreased very slowly with a terminal half life of 4476 h (187 day). The uveal tract concentrations at 24 weeks were still high (67.75 +/- 6.19 micrograms equiv g-1). The AUC for uveal tract was 842.3 mg.h g-1. A relatively high concentration was still determined in the uveal tract even at 48 weeks after single oral dosing by whole-body autoradiography. The uveal tracts separated from one eye of each rat were extracted with 0.067 M phosphate buffer (pH 7.4) and 1 M HCl-EtOH (30:70) successively. In pigmented rats, almost all radioactivity was released from the tissue with 1 M HCl-EtOH (30:70), indicating that the strong binding by melanin was reversible, and that hydrophobic or electrostatic interaction would play a critical role in the binding of chloroquine and its metabolites with the melanin-containing ocular tissues. Approximately 70% of the radioactivity given was recovered in urine and faeces up to 144 h after dosing both in pigmented and albino rats. The excretion pattern in pigmented rats was similar to that seen in albino rats.